From genetic sequence to phenotypic consequence: Genetic and environmental links between cognitive ability, socioeconomic position, and health

Cognitive ability is predictive of socioeconomic position (SEP), and health, with a higher level of cognitive ability being associated with a higher SEP, and lower risk of illness, and common genetic variants, in part, explain this link. The goal of this programme of research is to identify the regions of the genome (loci) and biological systems underlying this relationship, including those on the, as yet, unexamined mitochondrial genome, to quantify the genetic and environmental contributions to the relationship between cognitive ability, health, and SEP, and identify instances where these relationships are likely to be causal.
The elucidation of which genetic variants are linked to cognitive differences has proceeded rapidly in the last 5 years. However, genome-wide association studies (GWAS) have four issues that limit their use. These issues include a constraint on the sample size due to the difficulty in measuring cognitive ability, the absence of the mitochondrial genome from association studies, not adequately examining causal relationships between traits, and that interpretations of the effects identified using GWAS focus of genetic effects, despite the known presence of non-direct (or environmental effects) that result in trait variation.
My research programme will utilise creative, and novel techniques coupled with new data from the international collaborations I have forged to address unanswered questions pertaining to the genetic and environmental contributions to cognitive ability and its overlap with health and SEP. Specifically, I will generate the largest GWAS data set on cognitive ability using a design that allows for the combination of genetically linked phenotypes. The additional power afforded by this design will allow for more loci, associated specifically with cognitive ability, to be identified. These data will also be used to examine the biological systems and mechanisms that, once perturbed by genetic variation, are associated with differences in cognitive ability.
Unlike previous genetic investigations of cognitive ability I will also be examining the mitochondrial genome for association with cognitive ability. This novel analysis will also be used to examine the health traits that are associated with differences in cognitive ability to determine if the same loci in the mitochondrial genome is associated with both. This would provide a, partial, explanation for the link between cognitive ability, SEP, and health.
The loci identified in the multivariate design will next be used as genetic instruments in a series of Mendelian randomisation (MR) studies to examine causality. MR will be used to identify the causal role that cognitive ability plays in health differences as well as differences in brain imaging traits.
Finally, the role of the environment will be examined using family based cohorts and the genetic variants a parent does not share with their child. These non-transmitted genetic variants function in an analogous manner to the genotype of an adoptive parent, i.e. they may contribute towards the environment a child is raised in, but are independent to any genetic effects. By deriving genetic predictors based on these non-transmitted genetic variants I will be able to ascertain if the environmental effects of parental cognitive ability is associated with the offspring's level of cognitive ability and their health in later life.
These topics are important for expanding our knowledge of how cognitive ability and health are linked. By increasing statistical power, as well as including non-examined regions of the genome in my work we can have the best understanding of how genetic factors contribute towards cognitive and health differences. Furthermore, the use of MR and non-transmitted genetic effects will allow us to investigate the environmental consequences of cognitive ability on health and the health of the next generation.

Cognitive ability is phenotypically and genetically associated with health, mental health, and socioeconomic position (SEP). This research programme will examine this relationship to identify specific loci and biological mechanisms underlying this relationship, including those found on the, as yet, unexamined mitochondrial genome, to quantify the genetic and environmental contributions to the relationship between cognitive ability, health, and SEP, and identify instances where these relationships are likely to be causal. This research programme begins with a multivariate analysis of cognitive ability and genetically linked traits using genomic structural equation modelling in order to maximise statistical power and loci discovery. The loci identified will next be used to predict phenotypic variance in health, and cognitive ability in a family based cohort. Here, I will derive genetic predictors based on the alleles a parent has, but the offspring do not. This design will enable me to quantify the variation in cognitive ability, SEP, and health, that is attributable to the parental level of cognitive ability. Crucially the effect of these genetic predictors can be used to measure effects that are independent from any direct genetic effect between parent and offspring. Genetic instruments will next be created using the summary data from the multivariate analysis of cognitive ability. These will be used in Mendelian randomisation studies to examine the causal role that differences in cognitive ability play in health, SEP, and brain imaging traits. Finally, I will be the first to examine the role that genetic variation in the mitochondria is associated with differences in cognitive ability. This series of analysis will also include health, SEP, and brain imaging traits that are phenotypically associated with differences in cognitive ability, in order to examine if pleiotropic variants on the mitochondrial genome, contribute towards these phenotypic links.

The key aim of this programme of research is to understand the environmental and genetic links between cognitive ability and health, including instances where cognitive ability is a causal factor in disease and psychiatric risk. Due to the aims of this research programme it is likely to benefit clinicians, as well as the broader community.


1. Impact on clinicians. One of my primary goals is to understand the causal relationship between cognitive ability, health and mental health. This will have direct relevance for clinicians working in any of these fields as they will be better placed to identify individuals who are at risk. Furthermore, this programme will identify the degree to which parental cognitive ability is associated with offspring cognitive ability, independent of any direct genetic effect (i.e. Parents and their children sharing the alleles that give rise to their own level of cognitive ability). A better understanding of the magnitude of the effect of the environment will indicate how much environmental intervention is likely to raise cognitive ability. Finally, the results of the multivariate GWAS on cognitive ability will help identify some of the biological mechanisms that once perturbed by common genetic variation are associated with individual differences in cognitive ability. With this information we will be in a better position to identify the actionable mechanisms that may be targets for intervention.

2. Impact on the broader community. The work I have produced examining the genetic contributions to cognitive ability and health has been widely reported on in the press, as well as in the New Scientist, and Wired magazine. This wide interest in the topic of genetics, cognitive ability, and health, creates the opportunity to engage with, and educate, the public as to the nature of these findings. I have written extensive FAQs for my papers and ensured that these have been disseminated to the press. I will actively disseminate the results of this programme of research to the public at public lectures, through social media, as well as continue to generate press releases, FAQs and be interviewed by journalists.